Remodeling Intestinal Microbiota Alleviates Severe Combined Hyperlipidemia-Induced Nonalcoholic Steatohepatitis and Atherosclerosis in LDLR-/- Hamsters.

Combined hyperlipidemia (CHL) manifests as elevated cholesterol and triglycerides, associated with fatty liver and cardiovascular diseases. Emerging evidence underscores the crucial role of the intestinal microbiota in metabolic disorders. However, the potential therapeutic viability of remodeling the intestinal microbiota in CHL remains uncertain. In this study, CHL was induced in low-density lipoprotein receptor-deficient (LDLR-/-) hamsters through an 8-week high-fat and high-cholesterol (HFHC) diet or a 4-month high-cholesterol (HC) diet. Placebo or antibiotics were administered through separate or cohousing approaches. Analysis through 16S rDNA sequencing revealed that intermittent antibiotic treatment and the cohousing approach effectively modulated the gut microbiota community without impacting its overall abundance in LDLR-/- hamsters exhibiting severe CHL. Antibiotic treatment mitigated HFHC diet-induced obesity, hyperglycemia, and hyperlipidemia, enhancing thermogenesis and alleviating nonalcoholic steatohepatitis (NASH), concurrently reducing atherosclerotic lesions in LDLR-/- hamsters. Metabolomic analysis revealed a favorable liver lipid metabolism profile. Increased levels of microbiota-derived metabolites, notably butyrate and glycylglycine, also ameliorated NASH and atherosclerosis in HFHC diet-fed LDLR-/- hamsters. Notably, antibiotics, butyrate, and glycylglycine treatment exhibited protective effects in LDLR-/- hamsters on an HC diet, aligning with outcomes observed in the HFHC diet scenario. Our findings highlight the efficacy of remodeling gut microbiota through antibiotic treatment and cohousing in improving obesity, NASH, and atherosclerosis associated with refractory CHL. Increased levels of beneficial microbiota-derived metabolites suggest a potential avenue for microbiome-mediated therapies in addressing CHL-associated diseases.

Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters.

Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs). Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated. Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features. Then, the ApoA5-deficient (ApoA5-/-) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD). Results: ApoA5-/- hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue. An HFD challenge predisposed ApoA5-/- hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH). Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively. Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5-/- hamsters significantly ameliorated fatty liver without affecting plasma lipid levels. Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5-/- hamsters. Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future.

Clinical and Histopathological Features of Congenital Fibrovascular Pupillary Membranes in a Chinese Case Series.

PURPOSE: To investigate the clinical and histopathological features of congenital fibrovascular pupillary membrane (CFPM) in Chinese patients. METHODS: This retrospective study reviewed CFPM cases treated at Beijing Children's Hospital. The clinical manifestations, approaches of treatment, outcomes, and histopathological findings were collected and analyzed. RESULTS: A total of 33 patients with CFPM were reviewed. All patients had unilateral eye involvement. A total of 21 eyes (63.64%) had a white membrane that partially covered the pupil and 12 eyes (36.36%) had a membrane that completely covered the pupil. Of the 12 eyes with a complete pupillary membrane, 6 (50%) had glaucoma. For eyes with a partial pupillary membrane, 11 eyes (52.38%) were followed up at the outpatient clinic without surgery and 10 eyes (47.62%) underwent membranectomy and pupilloplasty due to visual axis blockage. For the 12 eyes with a complete pupillary membrane, 6 eyes (50%) with normal intraocular pressure (IOP) received membranectomy and pupilloplasty combined with iridectomy, and 1 (16.67%) of these 6 eyes underwent a reoperation after 5 months due to a recurrent membrane. Furthermore, 6 eyes (50%) with glaucoma had membranectomy, pupilloplasty, iridectomy, and goniosynechialysis. Among these 6 eyes, 2 eyes (33.33%) underwent a reoperation due to the recurrence of a membrane and 4 eyes (66.67%) had a pale optic disc. The histopathological findings revealed that these membranes were mainly composed of fibrous tissue, lymphocytes, pigment epithelial cells, and vascular tissues. CONCLUSIONS: CFPM has diverse manifestations, including a partial pupillary membrane, a complete pupillary membrane with normal IOP, and a complete pupillary membrane with glaucoma. Timely diagnosis and treatment are critical when the visual axis is blocked and/or the IOP is high. [J Pediatr Ophthalmol Strabismus. 2021;58(2):105-111.].

A DNA Damage-Repair Dynamic Model for HRS/IRR Effects of C.elegans Induced by Neutron Irradiation.

Neutron irradiation which could trigger severe biological effects, is being applied in nuclear plants, radiotherapy, and aerospace gradually. Low dose hyper-radiosensitivity response of low Linear Energy Transfer (LET) irradiation on the cell survival has become a matter of great interest since its discovery, but a few research have been done on this response induced by neutron irradiation. To investigate this response induced by neutron irradiation, Caenorhabditis elegans (C. elegans) was irradiated by neutron irradiation. The surviving fraction of C. elegans on the 12th day after irradiation was analyzed, which showed a hyper-radiosensitive response at low doses and followed by an increase in survival fraction at slightly higher doses. The finding of this work that neutron irradiation decreased the surviving fraction in a non-dose-dependent manner was different from previous low-LET irradiation studies. To understand the experimental results, a DNA damage-repair model was introduced. By comparing experimental results with theoretical analyses, we suggest that the low dose hyper-radiosensitivity response of neutron irradiation may possible related to different radiation types and DNA damage recognition proteins and immune system of C. elegans.

Enhancing wavefront estimation accuracy by using higher-order iterative compensations in the Southwell configuration.

Accurate wavefront integration based on gradient fields is crucial for various indirect measurement techniques, such as Shack-Hartmann sensing, shearography, and the fringe reflection technique. In this paper, a higher-order iterative compensation algorithm is proposed to enhance the reconstruction accuracy for the finite-difference-based least-squares integration (FLI) method. In this method, higher-order gradient fields are reconstructed and the calculated residual gradient fields compensate the truncation error with the traditional FLI by iterations. A comparison of different FLI methods, including traditional FLI, iterative FLI, higher-order FLI, and the proposed FLI method, is conducted. The result shows that the reconstructed wavefront with the proposed method is more accurate than those with other FLI methods. In addition, the impact of the gradient measurement noise is also discussed.

High-accuracy dithering-based three-dimensional data compression algorithms by phase correction.

The Holoimage technique can substantially reduce three-dimensional (3D) shape data sizes by converting the data into regular 24-bit 2D images. A dithering-based compression algorithm was recently proposed to further reduce the data size by only utilizing three bits to represent 3D shape data. However, our research finds that the recovery accuracy of the dithering-based algorithm is not very high due to the loss of information in the dithering process. In addition, we find that the final 3D recovery accuracy is highly related to the phase information. In this paper, to address the low accuracy problem, we propose two different phase-correction methods to store the phase-error information and retrieve the absolute phase with higher accuracy. Both methods can provide recovered 3D results with much better quality. Experimental results are presented to verify the performance of the proposed methods.